Degraders of WEE1 kinase

Abstract

Disclosed are bifunctional compounds (degraders) that target Wee1 tyrosine kinase for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat disease.

What is claimed is: 
     
       1. A compound having a structure represented by formula I: 
       
         
           
           
               
               
           
         
         wherein the targeting ligand is a moiety that binds Wee1 kinase and is represented by a structure selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         the degron is: 
       
       
         
           
           
               
               
           
         
       
       wherein Y′ is a bond, N, O or C; 
       
         
           
           
               
               
           
         
       
       wherein Z is a C 5 -C 6  carbocyclic or a C 5 -C 6  heterocyclic group; or 
       
         
           
           
               
               
           
         
       
       and
 the linker is an alkylene chain or a polyethylene glycol chain, either of which may be interrupted by and/or terminate (at either or both termini) in at least one of —O—, —S—, —N(R′)—, —C≡C—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(NOR′)—, —C(O)N(R′)—, —C(O)N(R′)C(O)—, —C(O)N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —OC(O)N(R′)—, —C(NR′)—, —N(R′)C(NR′)—, —C(NR′)N(R′)—, —N(R′)C(NR′)N(R′)—, —OB(Me)O—, —S(O) 2 —, —OS(O)—, —S(O)O—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —N(R′)S(O) 2 —, —S(O) 2 N(R′)—, —N(R′)S(O)—, —S(O)N(R′)—, —N(R′)S(O) 2 N(R′)—, —N(R′)S(O)N(R′)—, C 3 -C 12  carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R′ is H or C 1 -C 6  alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or a pharmaceutically acceptable salt or stereoisomer thereof. 
 
     
     
       2. The compound of  claim 1 , which is represented by a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
       3. The compound of  claim 1 , wherein the degron is 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound of  claim 3 , which is represented by any one of the following structures: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
       5. The compound of  claim 4 , which is represented by a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
       6. The compound of  claim 1 , wherein the linker is represented by a structure selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 1 , wherein the degron is 
       
         
           
           
               
               
           
         
       
       wherein Y′ is a bond, N, O or C; 
       
         
           
           
               
               
           
         
       
       wherein Z is a C 5 -C 6  carbocyclic or a C 5 -C 6  heterocyclic group; or 
       
         
           
           
               
               
           
         
       
     
     
       8. The compound of  claim 1 , which is represented by a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts and stereoisomers thereof. 
     
     
       9. The compound of  claim 1 , which is: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts and stereoisomers thereof. 
     
     
       10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, and pharmaceutically acceptable carrier. 
     
     
       11. The compound of  claim 1 , wherein the linker is a C 2 -C 6  alkylene group. 
     
     
       12. The compound of  claim 11 , wherein the linker is a C 4  alkylene group. 
     
     
       13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and pharmaceutically acceptable carrier. 
     
     
       14. A method of treating a disease or disorder mediated by aberrant Wee1 kinase activity, comprising administrating a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof. 
     
     
       15. The method of  claim 14 , wherein the disease is a cancer. 
     
     
       16. The method of  claim 15 , wherein the cancer is ovarian cancer. 
     
     
       17. The method of  claim 14 , wherein the method further comprises administering the therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof to the subject in combination with a therapeutically effective amount effective amount of an additional chemotherapeutic agent. 
     
     
       18. The method of  claim 17 , wherein the additional chemotherapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor. 
     
     
       19. The method of  claim 18 , wherein the PARP inhibitor is Olaparib.